A novel mechanism of regulating common gamma chain (γc) cytokine signaling by a soluble form of γc

Thursday, October 11, 2012 — Poster Session IV

2:00 p.m. – 4:00 p.m.

Natcher Conference Center, Building 45

NCI

IMMUNO-14

* FARE Award Winner

Authors

M.A. Luckey

J.-H. Park

Abstract

The γc is the central signaling unit for a number cytokines, collectively known as γc cytokines. γc cytokine signaling is mainly regulated by cytokine-specific receptor α-chain expression levels, because γc expression is presumed to remain unchanged on T cells. In contrast to existing data, we here describe that γc expression is actively modulated during T cell activation and development. Specifically, γc expression is downregulated in DP thymocytes but re-induced upon positive selection. Importantly, we found that such lower γc expression is also partially regulated by a novel post-transcriptional mechanism. Specifically, a soluble form of γc (sγc) was generated by alternative splicing. sγc expression was significantly upregulated in autoimmune disease bearing mouse models and increased in Experimental Autoimmune Encephalomyelitis (EAE)-induced mice. Mechanistically, sγc enhanced in vitro Th17 differentiation by blocking IL-2 signaling. To identify its in vivo role, we generated sγc-overexpressing transgenic mice (sγcTg), in which naïve:memory T cell ratio was reduced and activated-CD4+ T cells skewed to Th17 cell type. In EAE, more severe autoimmune disease in sγcTg mice was induced compared to wildtype mice. Collectively, we identified sγc and its biological role in regulation of γc cytokine signaling.